Project Summary Understanding the molecular mechanisms involved in host defense against pathogens is important for the development of novel anti-infective therapies. Type I interferon (?/?) and type II interferon (IFN?) are potent cytokines involved in the regulation of multiple cellular processes, including anti-viral, anti-tumor, and immunomodulatory functions. IFNs signal through the JAK-STAT pathways to regulate the transcriptional activation of over 2000 interferon-stimulated genes (ISGs). Studies from many laboratories have identified the important role of a number of ISGs in host defense against pathogens, including the IFN?-inducible 65kD guanylate-binding protein (GBP) family. However, the molecular mechanism that selectively regulates the induction of anti-infective ISGs during host defense is poorly understood. The Ten-eleven translocation (TET) family of proteins are methylcytosine dioxygneases that function to facilitate DNA demethylation through regulating cytosine hydroxymethylation. Previous studies have demonstrated that TET proteins play important roles in the regulation of stem cells and tumorigenesis. My laboratory has recently discovered an unexpected role of TET2 in host defense. We showed that Tet2 deficiency results in enhanced protection against bacterial and viral pathogens, and that TET2 specifically affects the induction of the Gbp genes in response to IFN? stimulation. This application is to explore a previously unrecognized role of TET2 in in IFN signaling and host defense against pathogenic infection. We propose to test a novel hypothesis that TET2 functions to suppress host immunity through the selective regulation of a subset of IFN-mediated gene transcription. Specifically, we will study the molecular basis of TET2-mediated regulation of Gbp genes in host defense, and we will further characterize the role of TET2 in pathogenic infections using animal models. These timely studies, if successfully completed, will uncover a novel molecular mechanism in host defense, and will advance our ability to design more effective anti- infective therapies.